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Metformin (Met), which is an insulin-sensitizer, decreases insulin resistance and fasting insulin levels. The precise molecular target of Met is unknown; however, several reports have shown an inhibitory effect on mitochondrial complex I of the electron transport chain (ETC), which is a related site for reactive oxygen species production. In addition to peripheral effects, Met is capable of crossing the blood-brain barrier, thus regulating the central mechanism involved in appetite control. The present study explores the effects of intracerebroventricular (i.c.v.) infusion of Met on ROS production on brain, insulin sensitivity and metabolic and oxidative stress outcomes in CF1 mice. Metformin (Met 50 and 100 µg) was injected i.c.v. in mice daily for 7 days; the brain mitochondrial H2O2 production, food intake, body weight and fat pads were evaluated. The basal production of H2O2 of isolated mitochondria from the hippocampus and hypothalamus was significantly increased by Met (100 µg). There was increased peripheral sensitivity to insulin (Met 100 µg) and glucose tolerance tests (Met 50 and 100 µg). Moreover, Met decreased food intake, body weight, body temperature, fat pads and survival rates. Additionally, Met (1, 4 or 10 mM) decreased mitochondrial viability and increased the production of H2O2 in neuronal cell cultures. In summary, our data indicate that a high dose of Met injected directly into the brain has remarkable neurotoxic effects, as evidenced by hypothermia, hypoglycemia, disrupted mitochondrial ETC flux and decreased survival rate.

Hyperpalatable diets (HP) impair brain metabolism, and regular physical exercise has an apparent opposite effect. Here, we combined a prior long-term exposure to HP diet followed by physical exercise and evaluated the impact on some neuroenergetic components and on cognitive performance. We assessed the extracellular lactate concentration, expression of monocarboxylate transporters (MCTs), pyruvate dehydrogenase (PDH), and mitochondrial function in the hippocampus. Male C57BL/6J mice were fed 4 months with HP or a control diet. Subsequently, they were divided in the following groups: control diet sedentary (CDS), control diet exercise (CDE), HP diet sedentary (HPS), and HP diet exercise (HPE) (n = 15 per group) and were engaged for an additional 30-day period of voluntary exercise and HP diet. Relative to the control situation, exercise increased MCT1, MCT4, and PDH protein levels, while the HP diet increased MCT1 and MCT4 protein levels. The production of hydrogen peroxide (HO) and the mitochondrial membrane potential (∆Ѱ) stimulated by succinate in hippocampal homogenates were not significantly different between groups. ADP phosphorylation and the maximal respiratory rate induced by FCCP showed similar responses between groups, implying a normal mitochondrial function. Also, extracellular brain lactate levels were increased in the HPE group compared to other groups soon after performing the Y-maze task. However, such enhanced lactate levels were not associated with improved memory performance. In summary, hippocampal protein expression levels of MCT1 and 4 were increased by physical exercise and HP diet, whereas PDH was only increased by exercise. These observations indicate that a hippocampal metabolic reprogramming takes place in response to these environmental factors.

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. We investigated the effect of a prior 30 days voluntary exercise protocol on STZ-diabetic CF1 mice. Glycemia, and the liver and skeletal muscle glycogen, mitochondrial function, and redox status were analyzed up to 5 days after STZ injection. Animals were engaged in the following groups: Sedentary vehicle (Sed Veh), Sedentary STZ (Sed STZ), Exercise Vehicle (Ex Veh), and Exercise STZ (Ex STZ). Exercise prevented fasting hyperglycemia in the Ex STZ group. In the liver, there was decreased on glycogen level in Sed STZ group but not in EX STZ group. STZ groups showed decreased mitochondrial oxygen consumption compared to vehicle groups, whereas mitochondrial H O production was not different between groups. Addition of ADP to the medium did not decrease H O production in Sed STZ mice. Exercise increased GSH level. Sed STZ group increased nitrite levels compared to other groups. In quadriceps muscle, glycogen level was similar between groups. The Sed STZ group displayed decreased O consumption, and exercise prevented this reduction. The H O production was higher in Ex STZ when compared to other groups. Also, GSH level decreased whereas nitrite levels increased in the Sed STZ compared to other groups. The PGC1 α levels increased in Sed STZ, Ex Veh, and Ex STZ groups. In summary, prior exercise training prevents hyperglycemia in STZ-mice diabetic associated with increased liver glycogen storage, and oxygen consumption by the mitochondria of skeletal muscle implying in increased oxidative/biogenesis capacity, and improved redox status of both tissues. J. Cell. Biochem. 118: 678-685, 2017. © 2016 Wiley Periodicals, Inc.

Background Obesity has become a global public health issue and is knowingly associated with several pathological conditions. Epidemiological data indicate it is an important risk factor for the development of neurodegenerative diseases, such as Alzheimer’s Disease (AD). However, the pathological mechanisms connecting these two conditions are still elusive. Current evidence points toward glucose metabolism dysregulation, as well as defective insulin signaling and low grade inflammation. Objective: Our main goal was to investigate the effects of a highly palatable diet (HPD) on brain glucose metabolism. Hypothesis: We hypothesized that the obesity induced by the HPD could lead to alterations in brain glucose metabolism similar to those found in AD. Methods Male C57BL/6J mice (45 days old) were fed with HPD (rich in simple sugars and fat) for four months. They were then examined in vivo via microPET [18F]FDG. Data from images were used to assemble [18F]FDG‐derived brain metabolic networks. A glucose tolerance test (GTT) was also performed to assess peripheral insulin response. Post‐mortem, the brain tissue was used in a high resolution respirometry test to evaluate mitochondrial activity. Results HPD animals presented increased body weight (HPD= 37.17±4.38g; control= 28.72±1.23g; P<0.0001) and abnormal peripheral tolerance to glucose (peak blood glucose: HPD=421.93±47.13mg/dL; control=323.60±43.83mg/dL P<0.0001). HPD also induced [18F]FDG hypermetabolism in the prefrontal cortex and a hypersynchronicity in the metabolic network, where the hypothalamus appears to be more connected to the hippocampus, thalamus, prefrontal cortex, and striatum. Brain post mortem analysis indicated a less efficient mitochondrial oxidative phosphorylation in the hypothalamus of HPD fed animals as measured by the Respiratory Chain Ratio (HPD=0.640±0.022; control= 0.810±0.012 P<0.001). Conclusion These preliminary results show that HPD causes peripheral and central disturbances in glucose metabolism, also altering brain mitochondrial activity. Interestingly, in vivo imaging indicates that the prefrontal cortex is highly active and the hypothalamus is unusually connected to other brain regions in these animals.